Mycobacterium leprae, the causative agent of leprosy, has caused human disease since ancient times, yet remains an important endemic disease in some countries. Infection with M. leprae also provides a unique opportunity to study the innate immune system due to an unusual relationship between the host immune system and the infectious sequelae. The clinical manifestations of infection are polarized into one of two forms. The "tuberculoid" form shows a well-formed granulomatous response in affected tissues and is associated with a Th1 pattern of cytokine expression and limited disease. Alternatively, the "lepromatous" form is associated with a poor cellular immune response, a Th2 type of cytokine profile, and results in widespread lesions with a high mycobacterial load. The factors which predispose individuals to these leprosy subtypes are largely unknown. Common genetic variations within components of the innate system have been associated with altered susceptibility to a number of bacterial and mycobacterial infections. It is hypothesized that such variations may help determine the type of immune response to M. leprae as well. Our preliminary work suggests that single nucleotide polymorphisms (SNPs) within LTA4H, of the leukotriene biosynthesis pathway, may be associated with "reactional states" that occur with rapid changes in the type of host immune response. Data on the forms of disease and histories of reactional states have already been recorded for 1421 patients with leprosy in Nepal. In order to determine the effect of such SNPs on disease manifestations, I will use a case control study design to compare the genotypes of these cases to those of uninfected controls. For any such relevant SNPs, the molecular and cellular mechanisms responsible for the clinical variations will be determined. First, the effect of M. leprae stimulation on the leukotriene pathway will be explored in vitro. Next, I will study the role of individual Toll-like Receptors (TLRs) in activation of leukotriene synthesis to probe for novel interactions between these two pathways as TLR SNPs are also associated with an altered immune response to M. leprae infection. Third, I will examine the role of LTA4H SNPs in these stimulation experiments using leukocytes from individuals of each genotype. Finally, I will assay for changes in the enzymatic activities of LTA4H due to these variants in vitro. Leprosy offers a unique model in which to study the establishment of the Th1 or Th2 adaptive immune response. Genetic variations of the innate immune system components likely predispose to such responses and will offer insight into this poorly understood process. An awareness of how common variants alter the immune response has broad implications for both human infectious and inflammatory diseases.